Topical personal care compositions must be formulated at a skin-tolerant pH range, but many of the cosmetically beneficial compounds have very low solubility at that pH, their solubility being substantially higher at a very alkaline or very acidic pH, outside of the pH range tolerated by skin. Some examples of such compounds are salicylic acid, fumaric acid, azelaic acid, sorbic acid, uric acid, alginic acid, amino acids and other zwitterionic compounds such as for example tyrosine, isoleucine, tryptophan, phenylalanine. One of such compounds, for example, is cystine. This is unfortunate because cystine can serve as a building block for glutathione production in the body. Glutathione (GSH) is a tripeptide that consists of glutamate, cysteine, and glycine. It is present in all mammalian tissues. It is the main anti-oxidant in the living body: it protects cells from oxidation by quenching reactive oxygen species. GSH is believed to play a significant role in protecting cells against the cytotoxic effects of ionizing radiation, heat, certain chemicals, and significantly, solar UV radiation (Tyrell et al., Photochem. Photobiol. 47: 405-412, 1988; Meister, J. Biol. Chem. 263: 205-217, 1988; Meister, Science 200:471-477, 1985). While true in all areas of the body, this is particularly important in the skin, which is so greatly exposed to the damaging effects of radiation, particularly UV radiation, and environmental pollutants. Decrease in the intracellular concentration of glutathione in skin is associated with cell damage, inflammation, skin darkening, discoloration, spots or freckles caused by exposure to ultraviolet radiation, physiological aging, and the like. It is, therefore, highly desirable to enhance the generation of glutathione in skin.
A logical approach would seem to be to provide cells with an exogenous source of GSH (e.g. through ingestion or topical delivery). Unfortunately, GSH is not bioavailable when administered exogenously, i.e. where localized extracellularly, it is broken down into its constituent amino acids (glutamate, cysteine, and glycine) for cellular uptake and synthesis of the GSH tripeptide. Thus, GSH is not directly transported into the cells and therefore does not itself result in an intracellular increase of glutathione. Biosynthesis of GSH occurs in the cell in a tightly regulated manner. The quantity of glutathione in cells depends to a large degree on the availability of cysteine in the cells. Cysteine, a composite amino acid of GSH, may increase cellular levels of GSH, but exposed sulfhydryl group of cysteine renders it unstable and reactive and also causes strong unpleasant odor. Unlike cysteine, cystine can be administered safely; cystine is transported into the cell and converted to cysteine within the cell, the cysteine then being available for intracellular GSH production.
Topical compositions containing various amino acids and other skin care actives have been described, see e.g. Tanojo U.S. Pat. No. 7,300,649B2, Laboratoire Filorga product, Schlachter WO 00/03689, Ermolin et al. US2011183040, Garlen et al. U.S. Pat. No. 4,707,354, Muller et al. U.S. Pat. No. 8,361,446, Hermann et al. U.S. Pat. No. 8,241,681. Compositions for potentiating intracellular glutathione production have been described. See e.g. Chiba et al. U.S. Pat. No. 7,740,831, Crum et al (USRE37934, USRE42645, WO2016/033183, and US20050271726); Mammone U.S. Pat. No. 6,149,925, and Perricone US 20060063718.
Cystine is normally derived from the diet. Delivery of cystine from topical compositions, however, is challenging due to its extremely low solubility in biologically acceptable vehicle at a skin-tolerant pH range. The solubility of cystine in water is 0.112 mg/ml at 25° C.; cystine is more soluble in aqueous solutions with pH less than 2 or pH above 8. Efforts have been made to increase L-Cystine solubility. See e.g. Erich Königsberger, Zhonghua Wang, Lan-Chi Königsberger Solubility of L-Cystine in NaCl and Artificial Urine Solution; Monatshefte für Chemie, January 2000, Volume 131, Issue 1, pp 39-45; Hsieng-Cheng TsengHsieng-Cheng Tseng et. al, Solubilities of amino acids in water at various pH values under 298.15 K, Fluid Phase Equilibria 285(1):90-95⋅October 2009; F. Apruzzese, et. al Protonation equilibria and solubility of L-Cystine, Talanta, 56, 459-469, 2002; C. Bretti, et. al Solubility and activity coefficients of acidic and basic noneelectrolytes in aqueous salt solutions. J. Chem. Eng. Data, 50, 1761-1767, 2005; Michael D. Ward, Jeffrey D. Rimer, U.S. Pat. No. 8,450,089; Michael D. Ward, Zina Zhou, U.S. Pat. No. 8,916,609; Hara, et. al U.S. Pat. No. 5,316,767; Longqin Hu, US 2014/0187546.
The present invention is based in part on a surprising finding that compounds, such as cystine, may be solubilized in topical personal care compositions at a skin tolerant pH range, at substantially the same level as cystine's solubility at high or low pH.